Hamster cheekpouches treated topically with 6% nicotine and dimethylbanzanthracene (DMBA) developed significantly more tumors than those treated with DMBA alone (Chen and Squier, J. Nat. Canc. Inst. 82:861, 1990). One explanation for this finding may be that nicotine damages the epithelial barrier, permitting greater access by carcinogens. To test this hypothesis, we treated the cheekpouches of 20 hamsters with 25ul of 6% nicotine daily; 8 controls were treated with sesame oil only. After 8 weeks and 20 weeks, 10 experimental and 4 control animals were killed and the cheek pouches examined histologically. Permeability constants (Kp+SE10-7cm/min) to tritiated water and DMBA were also determined using perfusion chambers. Histologically, cheekpouch epithelium of experimental animals showed hyperplasia and hyperkeratosis at both tome intervals. Permeability to water was increased significantly in experimental animal (646+31) compared to controls (312+19) at 8 weeks and this was maintained at 20 weeks (456+29 and 337+22 respectively). However, values for DMBA were only significantly different (p<0.05) in experimental animals at 20 weeks (66+5) as compared to controls (54+3). The increased permeability may be associated with the hyperkeratotic changes seen after chronic nicotine treatment; a similar outcome has been described for hamster cheekpouch treated with hyperplasiogens (Squier and Hall, J. Oral Path 14:357, 1985). Supported by and AADR Student Research Fellowship (H.A. Reid) and R01 DE07930.